ReviewCardiovascular Disease

Cardiac differentiation of pluripotent stem cells and implications for modeling the heart in health and disease

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Science Translational Medicine  04 Apr 2018:
Vol. 10, Issue 435, eaah5457
DOI: 10.1126/scitranslmed.aah5457


  • Fig. 1 Gene expression during human heart development.

    Shown are the key genes expressed in various compartments of the human heart. The genes depicted are essential for regional identity and cardiac function, and their expression is dependent on the stage of cardiac development. This genetic blueprint for heart development is crucial for proper identification and characterization of human pluripotent stem cell (hPSC)–derived cardiomyocyte (CM) subtypes. AVB, atrioventricular bundle; BB, bundle branches.

    Credit: A. Kitterman/Science Translational Medicine
  • Fig. 2 Methods to generate mature hPSC-derived CMs in vitro.

    Structural, functional, and metabolic characteristics of hPSC-derived CMs resemble those of fetal human CMs but not of adult human CMs. hPSC-derived CMs can be driven toward a more mature adult CM phenotype by (left) the addition of tri-iodo-l-thyronine (T3) thyroid hormone to the culture medium, (middle) by coculture with nonmyocyte cell types such as endothelial cells, or (right) by applying electrical stimulation or cycles of mechanical stress to the hPSC-derived CMs in culture.

    Credit: A. Kitterman/Science Translational Medicine
  • Fig. 3 Tissue engineering strategies to build a human heart in vitro.

    (Left) Engineered heart tissue can be generated by growing hPSC-derived CMs in a hydrogel system. (Middle) Engineered heart tissue has been generated from decellularized rat, pig, or human hearts that formed scaffolds, which were then repopulated by cardiac cells derived from hPSCs. (Right) In the future, hPSC-derived cardiac progenitor cells or cardiac cell subtypes will be bioprinted onto a three-dimensional (3D) heart scaffold to generate mini hearts in vitro.

    Credit: A. Kitterman/Science Translational Medicine


  • Table 1 Functional properties and diseases associated with different CM subtypes.

    Cardiac subtypeAction potential shapePropertiesAssociated diseases
    Sinoatrial nodal cellsEmbedded ImageSpontaneous depolarization; slow
    action potential upstroke mediated
    by calcium currents and almost
    complete absence of fast sodium
    currents; lacks IK1 current but has
    prominent If current
    Sinus bradycardia, sinoatrial block,
    bradycardia-tachycardia syndrome
    Atrioventricular nodal cellsEmbedded ImageSimilar to the sinoatrial nodal cells
    but with slower intrinsic rate
    Atrioventricular block,
    atrioventricular nodal reentrant
    Atrial cellsEmbedded ImageMore negative resting membrane
    potential compared to pacemaker
    cells; shorter action potential
    duration compared to ventricular
    CMs; prominent IKur and IKACh
    Atrial fibrillation
    Ventricular cellsEmbedded ImageAction potentials with a clear plateau
    phase; prominent IK1, IKr, and IKs
    currents; transmural heterogeneity
    Rhythm disorders (long QT
    syndrome, LEOPARD syndrome,
    catecholaminergic polymorphic
    ventricular tachycardia),
    cardiomyopathies (hypertrophic
    cardiomyopathy, dilated
    cardiomyopathy, arrhythmogenic
    right ventricular cardiomyopathy)
    Purkinje cellsEmbedded ImageLonger action potentials with a more
    negative plateau phase;
    prominent Ito current compared to
    ventricular CMs
    Congenital histiocytoid
  • Table 2 Generating cardiac cell subtypes from PSCs.

    hESCs, human embryonic stem cells; mESCs, mouse embryonic stem cells; hiPSCs, human induced pluripotent stem cells; FGF, fibroblast growth factor; BMP4, bone morphogen protein 4; TGF-β, transcription growth factor–β; WNT, wingless/integrated; cAMP, cyclic adenosine 3′,5′-monophosphate.

    Cardiac subtypeSourceApproach
    node–like cells
    mESCsOverexpression of Tbx3, overexpression of Shox2
    hESCs/hiPSCsInhibition of FGF/BMP signaling in cardiac progenitor cells generated an NKX2.5/Podoplanin+ population
    that gave rise to sinoatrial node–like cells upon differentiation
    hESCs/hiPSCsActivation of BMP/retinoic acid signaling plus inhibition of FGF, TGF-β, and WNT signaling
    Atrial-like cellsmESCs/hESCsActivation of retinoic acid signaling
    mESCsGremlin-based inhibition of BMP signaling
    Ventricular-like cellshESCsInhibition of retinoic acid signaling
    hiPSCsInhibition of WNT signaling
    Purkinje cellsmESCsActivation of cAMP signaling

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